Selenium has been implicated in immunological function and many other biological processes through various nutritional and biochemical studies (Lee et al., 1997, Molecules & Cells 6:509-20; Hatfield et al., 1999, Comprehensive Natural Products Chemistry, 4, 353-80; Gladyshev and Hatfield, 1999, J. Biomed. Sci., in press). Recent studies have shown that supplementation of the diet with selenium resulted in 63% reduction in human prostate cancer and, to a lesser extent, in the reduction of colon and lung cancers (Clark et al., 1996, JAMA, 276:1957-63).
Selenium, a trace element, is a natural component of several prokaryotic and eukaryotic proteins. Although selenium occurs in prokaryotic proteins either as a cofactor or as a selenocysteine residue, mammalian selenoproteins identified thus far contain selenium only in the form of selenocysteine, which is the 21st naturally occurring amino acid in protein. A selenocysteine tRNA that decodes UGA has been found in all life kingdoms, suggesting that the use of UGA as a codon for selenocysteine is widespread in nature (Hatfield and Diamond, 1993, Trends Genet. 9:69-70). The special conserved stem-loop structures in the 3′-untranslated regions of mammalian selenoprotein mRNAs are essential for recognition of UGA as a codon for selenocysteine, rather than a codon for termination of translation (Low and Berry, 1996, Trends Biochem. Sci. 21:203).
Of the eleven genes encoding different selenocysteine-containing proteins that have been found thus far in mammals, four encode various glutathione peroxidases (reviewed in Sunde, 1994, In: Selenium in Biology in Human Health, ed. Burk, R. F. (Springer, New York), pp. 146-77; and Ursini et al., 1995, Methods Enzymol. 252:38-53), three encode different thyroid hormone deiodinases (Berry et al., 1991, Nature, 349:438; Croteau et al., 1996, J. Clin. Invest. 98:405; and St. Germain et al., 1994, Proc. Natl. Acad. Sci. USA, 91:7767), and others encode thioredoxin reductase (Gasdaska et al., 1995, FEBS Lett. 373:5), selenophosphate synthetase 2 (SPS2) (Guimaraes et al., 1996, Proc. Natl. Acad. Sci. USA 93:15086-91), selenoprotein P (Hill and Burk, 1994, In: Selenium in Biology in Human Health, ed. Burk, R. F. (Springer, New York), pp. 117-32) and selenoprotein W (Vendeland et al., 1995, Proc. Natl. Acad. Sci. USA 92:8749).
Selenocysteine is located at the active center and is directly involved, or at least implicated, in the catalytic reactions catalyzed by glutathione peroxidases, thyroid hormone deiodinases and selenophosphate synthetase 2. Thioredoxin reductase contains selenocysteine (Tamura and Stadtman, 1996, Proc. Natl. Acad. Sci. USA, 93:1006-11) in a novel C-terminal Gly-Cys-Sec-Gly redox motif (Gladyshev et al., 1996, Proc. Natl. Acad. Sci. USA 93:6146-51). This center has been implicated in the peroxidase reaction catalyzed by the enzyme (Gladyshev et al., 1996, Proc. Natl. Acad. Sci. USA 93:6146-51) and in a redox interaction with the N-terminal redox disulfide (Arscott et al., 1997, Proc. Natl. Acad. Sci. USA 94:3621-6), although further studies are necessary to prove the suggested essential role of selenocysteine in this protein. Selenoprotein P, a protein of unknown function, is unusual in that it contains ten selenocysteine residues. The function of selenoprotein W also remains unknown.
None of the previously characterized selenoproteins is a likely candidate to account for the selenium effect observed in the reported cancer studies. The present invention is directed towards a newly isolated selenoprotein that is differentially expressed in tumor cells.